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Multiple myeloma

This x-ray shows the punched-out lytic lesions common to multiple myeloma, a disease characterized by the neoplastic proliferation of plasma cells. ​The dysregulation of osteoblast function causes hypercalcemia, and the deposition of light chain proteins in the renal tubules causes renal impairment. This characteristic appearance of the skull on x-ray is sometimes referred to as salt and pepper skull, or pepper pot skull.

Multiple myeloma is the most common primary malignant bone neoplasm in adults. It arises from red marrow due to monoclonal proliferation of plasma cells and manifests in a wide range of radiographic abnormalities. Multiple myeloma remains incurable.

Terminology
Four main patterns are recognised:

disseminated form: multiple well-defined “punched out” lytic lesions: predominantly affecting the axial skeleton
disseminated form: diffuse skeletal osteopenia
solitary plasmacytoma: a single large/expansile lesion most commonly in a vertebral body or in the pelvis
osteosclerosing myeloma
The remainder of this article relates to the disseminated forms. Please refer to the article plasmacytoma for discussion of the latter.

Smouldering multiple myeloma refers to a form that falls on the spectrum between monoclonal gammopathy of unknown significance (MGUS) and active multiple myeloma. Patients are asymptomatic, with worse biochemistry than MGUS but without the end-organ damage of active multiple myeloma 9.

Epidemiology
Multiple myeloma is a common malignancy in patients above 40 (70% of cases are diagnosed between ages 50 and 70) with a male predilection (M:F 2:1) 7. It accounts for 1% of all malignancies and 10% of all haematological disease. Multiple myeloma and osteosarcoma combined account for approximately 50% of all primary bone malignancies 7.

Clinical presentation
Clinical presentation of patients with multiple myeloma is varied, and includes 1-2,7:

bone pain
initially intermittent, but becomes constant
worse with activity/weight bearing, and this is worse during the day
anaemia
typically normochromic/normocytic
renal failure
proteinuria
hypercalcaemia
The presentation may also be with a complication, including:

pathological fracture
vertebral compression fracture
long bone fracture (e.g. proximal femur)
amyloidosis
recurrent infection: e.g. pneumonia due to leucopenia
plasmacytomas typically progress to multiple myeloma
The initial presentation occasionally is a polyneuropathy when it is part of a POEMS syndrome (mostly the sclerotic form).

Laboratory findings include:

reverse albumin/globulin ratio (i.e. low albumin, high globulin)
monoclonal gammopathy (IgA and/or IgG peak)
Bence Jones protein (Ig light chain) proteinuria
hypercalcaemia
decreased or normal ALP unless there is a pathological fracture due to impaired osteoblastic function
The most popular staging system, the International Staging System, uses the combination of β2-microglobulin test and serum albumin 6.

Approximately 1% of cases will have negative serum electrophoresis and negative urine Bence Jones protein.

Pathology
Multiple myeloma results from monoclonal proliferation of malignant plasma cells which produce immunoglobulins (commonly IgG) and infiltrate haemopoietic locations (i.e. red marrow).

Renal involvement is common and renal failure is multifactorial:

obstructive casts form in the renal tubules composed of Bence Jones proteins, immunoglobulins, albumin and Tamm-Horsfall proteins
the most common cause of renal failure in multiple myeloma
direct nephrotoxicity of Bence Jones proteins on the epithelial cells of the renal tubules
hypercalcaemia and dehydration
hyperuricaemia and urate nephropathy due to high cell turnover
amyloidosis (AL type)
increased risk of renal infection

Distribution
Distribution of multiple myeloma mirrors that of red marrow in the older individual, and thus this is mostly encountered in the axial skeleton and proximal appendicular skeleton:

vertebrae (most common)
ribs
skull
shoulder girdle
pelvis
long bones
extraskeletal structures (extraosseous myeloma): rare
Radiographic features
Radiology has a number of roles in the diagnosis and management for multiple myeloma:

suggest the diagnosis / exclude other causes
assess possible mechanical complications (e.g. pathological fracture)
assess disease progression
Disseminated multiple myeloma has two common radiological appearances, although it should be noted that initially, radiographs may be normal, despite the presence of symptoms. The two main diffuse patterns are:

numerous, well-circumscribed, lytic bone lesions (more common)
punched out lucencies
raindrop skull 7
endosteal scalloping
generalised osteopenia (less common)
often associated with vertebral compression fractures/vertebra plana
Plain radiograph
A skeletal survey is essential not only for the diagnosis of multiple myeloma but also in pre-empting potential complications (e.g. pathological fracture) and assessing response to therapy. A typical skeletal survey consists of the following films:

lateral skull
frontal chest film
cervical-thoracolumbar spine
shoulders
pelvis
femora
The vast majority of lesions are purely lytic, sharply defined/punched out, with endosteal scalloping when abutting the cortex. Lesions are sclerotic in only 3% of patients 7.

CT
CT does not have a major role in the diagnosis of disseminated multiple myeloma; however, it may be useful for determining the extent of the extraosseous soft tissue component in patients with a large disease burden.

It may also better assess the risk of fracture in severely affected bones.

MRI
MRI is generally more sensitive in detecting multiple lesions compared to the standard plain film skeletal survey. Infiltration and replacement of bone marrow are exquisitely visualised, and newer scanners are able to perform whole body scans for this purpose, shown to be superior to both CT and skeletal surveys 8.

Signal characteristics include:

T1
typically low signal
high-grade, diffuse involvement may become isointense to adjacent normal marrow
T2 with fat-suppression
high signal
T1 with contrast
​​hyperintense
early wash-in (highly vascular) and early wash-out (due to tightly packed plasma cells) is described 10
Nuclear medicine
Bone scintigraphy appearance of patients with disseminated multiple myeloma is variable due to the potential lack of osteoblastic activity. Larger lesions may be either hyperactive (hot) or photopenic (cold). Bone scans may also be normal. Therefore, bone scans usually do not contribute significant information to the workup of patients with suspected or established disseminated multiple myeloma, as the sensitivity of detecting lesions is less than that of a plain film skeletal survey 7.

PET-CT has had a growing role in the management of this disease, as it is effective in identifying the distribution of disease. 18F-FDG uptake by the myeloma lesions corresponds to areas of bone lysis seen on CT.

Treatment and prognosis
Currently, multiple myeloma remains incurable, although the introduction of thalidomide, lenalidomide and bortezomib (proteasome inhibitor) have provided significant survival gains 6. These are typically used in combination with older agents such as cyclophosphamide, melphalan, prednisolone and doxorubicin 6.

Treatment response is usually assessed by measuring serum markers and bone marrow sampling.

Stem-cell harvest and autologous stem cell transplant post-chemotherapeutic/radiotherapy bone marrow ablation are also used, although relapse is inevitable.

Differential diagnosis
The main differential is that of widespread bony metastases. Findings that favour the diagnosis of bone metastases over that of multiple myeloma include:

more commonly affect the vertebral pedicles rather than vertebral bodies
rarely involve mandible, distal axial skeleton
although both entities have variable bone scan appearances (both hot and cold) unlike myeloma, extensive bony metastases rarely have a normal appearance

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